DNA-dependent protein kinase (DNA-PK) permits vascular smooth muscle cell proliferation through phosphorylation of the orphan nuclear receptor NOR1

Medunjanin, Senad; Daniel, Jan‐Marcus; Weinert, Sönke; Dutzmann, Jochen; Burgbacher, Frank; Brecht, Sarah; Bruemmer, Dennis; Kähne, Thilo; Naumann, Michael; Sedding, Daniel; Zuschratter, Werner; Braun‐Dullaeus, Ruediger C.

doi:10.1093/cvr/cvv126

Cited by 27 publications

(29 citation statements)

References 33 publications

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“…Considering the reports from the existing experimental work, along with the predictions obtained from our prediction methods, it can be concluded that the sub-cellular localization of unliganded NURR1 resides in the nucleus. NOR1 (Neuron-derived Orphan Receptor 1, NR4A3) is reported to be localized in the nucleus of the cell in accordance with the experimental work done by Medunjanin et al, 2015 [65]. Immunostaining of human vascular smooth muscle cells were done in order to observe the subcellular localization.…”

Section: Nr4 Subfamilysupporting

confidence: 73%

A Comprehensive Analysis and Prediction of Sub-Cellular Localization of Human Nuclear Receptors

Mathew¹,

Thakur²,

Kumar³

et al. 2018

Nuclear Receptor Research

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The Nuclear Receptor (NR) superfamily comprises of conserved ligand-modulated intracellular transcription factors which in the presence of their cognate ligands activate a plethora of signaling networks, thereby commencing their respective transcription functions. All NRs are nuclear when liganded or active. However, their localization may differ between nucleus and cytoplasm when unliganded or inactive. NRs control a majority of physiological processes in body ranging from metabolism to reproduction and development. Hitherto, in case of humans, 48 NRs have been identified which are localized either in cytosolic, nuclear or both compartments of the cell. Sub-cellular localization of proteins has great relevance in relation to their function. However, specific sub-cellular localization patterns of human NRs are clouded with ambiguity and are mostly ridden with controversy, with only a few of them being well-studied and established under specific physiological conditions. In the present study, we attempted to bridge the gap and attempted to draw conclusions in relation to sub-cellular localization of human NRs based on published experimental data and by in-silico prediction methods. This comprehensive analysis may not only be useful to draw conclusions on their control of physiological processes but may also open new avenues towards understanding of the molecular basis of NR-mediated diseases attributed to their mislocalization and malfunctioning.

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Section: Nr4 Subfamilysupporting

confidence: 73%

A Comprehensive Analysis and Prediction of Sub-Cellular Localization of Human Nuclear Receptors

Mathew¹,

Thakur²,

Kumar³

et al. 2018

Nuclear Receptor Research

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“…HEK293, MCF-7, NIH3T3 and peripheral blood mononuclear cells cells were grown as described4853. Peripheral blood mononuclear cells (PBMNCs) were isolated as described53. Adherent cells were further cultivated for 14 days to obtain monocyte-derived macrophages.…”

Section: Methodsmentioning

confidence: 99%

GSK-3β controls NF-kappaB activity via IKKγ/NEMO

Medunjanin

Schleithoff

Fiegehenn

et al. 2016

Sci Rep

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The NF-κB signaling pathway is central for the innate immune response and its deregulation is found in multiple disorders such as autoimmune, chronic inflammatory and metabolic diseases. IKKγ/NEMO is essential for NF-κB activation and NEMO dysfunction in humans has been linked to so-called progeria syndromes, which are characterized by advanced ageing due to age-dependent inflammatory diseases. It has been suggested that glycogen synthase kinase-3β (GSK-3β) participates in NF-κB regulation but the exact mechanism remained incompletely understood. In this study, we identified NEMO as a GSK-3β substrate that is phosphorylated at serine 8, 17, 31 and 43 located within its N-terminal domain. The kinase forms a complex with wild-type NEMO while point mutations of NEMO at the specific serines abrogated GSK-3β binding and subsequent phosphorylation of NEMO resulting in its destabilization. However, K63-linked polyubiquitination was augmented in mutated NEMO explaining an increased binding to IKKα and IKKβ. Even IκBα was found degraded. Still, TNFα-stimulated NF-κB activation was impaired pointing towards an un-controlled signalling process. Our data suggest that GSK-3β is critically important for ordered NF-κB signalling through modulation of NEMO phosphorylation.

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“…Limits MDM2-TP53 interaction Control of smooth muscle proliferation (Medunjanin et al, 2015;Kinoshita et al, 2017) Maintenance of endothelial cell quiescence (Mannell et al, 2010) Increased level of myocardial expression in dilated cardiomyopathy (Bartunek et al, 2002) ERK1/2 Ser166 and Ser 186 Stabilizes MDM2, facilitates nuclear translocation Alterations of the ERK related pathway are involved in cardiovascular pathogenesis (Muslin, 2008) Akt/PKB Ser166 and Ser 186 Stabilizes MDM2, limits self-ubiquitination and degradation, facilitates nuclear localization Akt/PKB pathway is crucial regulator of cell survival, angiogenesis, vasodilation, metabolism in the cardiovascular system (Abeyrathna and Su, 2015) Cyclin A/CDK2 Thr216 Promotes MDM2-TP53 interaction Control of cell cycle in the cardiovascular system (Stanley-Hasnain et al, 2017) GSK-3 Ser240 and Ser254 Limits MDM2-TP53 interaction, inhibition of TP53 ubiquitination and degradation…”

Section: Dna-pk Ser17mentioning

confidence: 99%

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

Lam

Roudier

2019

Front. Cell Dev. Biol.

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The E3 ubiquitin ligase Murine double minute 2 (MDM2) is the main negative regulator of the tumor protein p53 (TP53). Extensive studies over more than two decades have confirmed MDM2 oncogenic role through mechanisms both TP53-dependent and TP53-independent oncogenic function. These studies have contributed to designate MDM2 as a therapeutic target of choice for cancer treatment and the number of patents for MDM2 antagonists has increased immensely over the last years. However, the question of the physiological functions of MDM2 has not been fully resolved yet, particularly when expressed and regulated physiologically in healthy tissue. Cardiovascular complications are almost an inescapable side-effect of anti-cancer therapies. While several MDM2 antagonists are entering phase I, II and even III of clinical trials, this review proposes to bring awareness on the physiological role of MDM2 in the cardiovascular system.

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DNA-dependent protein kinase (DNA-PK) permits vascular smooth muscle cell proliferation through phosphorylation of the orphan nuclear receptor NOR1

Abstract: DNA-PK directly phosphorylates NOR-1 and, this way, modulates SMC proliferation. These data add to our understanding of vascular remodelling processes and opens new avenues for treatment of vascular proliferative diseases.

Cited by 27 publications

References 33 publications

A Comprehensive Analysis and Prediction of Sub-Cellular Localization of Human Nuclear Receptors

A Comprehensive Analysis and Prediction of Sub-Cellular Localization of Human Nuclear Receptors

GSK-3β controls NF-kappaB activity via IKKγ/NEMO

Considering the Role of Murine Double Minute 2 in the Cardiovascular System?

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